5,6,7,4'-Tetramethoxyflavanone attenuates NADPH oxidase 1/4 and promotes sirtuin-1 to inhibit cell stress, senescence and apoptosis in Aß25-35–mediated SK-N-SH dysfunction

Amyloidogenesis is a fundamental step of amyloid beta (Aβ) generation-induced toxicity that is commonly reported to disrupt neuronal circuits, function and survival in Alzheimer's disease (AD). The neuroprotective effect of 5,6,7,4'-tetramethoxyflavanone (TMF) from Chormolaela odorata extract on brain degeneration and amyloidogenesis has previously been demonstrated. However, the mechanistic evidence for TMF's effects is still unclear. In this study, we evaluated the neuroprotective effect of TMF in Aβ(25-35)-induced toxicity in SK-N-SH neuroblastoma cells. Herein, we demonstrated that TMF exhibited potent antioxidant activity and significantly increased cell viability and decreased ROS production in a dose-dependent manner. Moreover, TMF reversed the effect of Aβ(25-35), which caused energy deprivation and apoptosis, by decreasing the ratio of Bax/Bcl-x(L) and reducing mitochondrial membrane potential (Δψ(m)), caspase-3 expression, apoptotic cells, and attenuating glucose transporter (Glut-3) expression. In addition, TMF protected against Aβ(25-35)-induced cellular senescence by attenuating β-galactosidase, p-21 and p-53 expression and promoted the expression of Sirt-1 and p-Rb. In addition, the effects of TMF on Aβ(25-35) toxicity were related to the upregulation of phase II antioxidant and nuclear factor erythroid 2-related factor-2 (Nrf2) signaling, including superoxide dismutase (SOD), heme oxygenase (HO)-1, and nuclear translocation of Nrf2. Finally, we also found that TMF attenuated Aβ(25-35)-reduced synaptic plasticity by increasing the expression of synaptophysin and PSD-95, which was correlated with a decrease in acetylcholine esterase (AChE). Importantly, we found that the protective effects of TMF on Aβ(25-35) were bidirectional, including marked inhibition of NADPH oxidase (NOX)-4 activity and partial activation of Sirt-1, which occurred prior to a reduction in the negative responses. Therefore, TMF may be useful for treating Aβ toxicity in AD.